Processes and intermediates useful to make antifolates

Abstract

The present application relates to a series of novel sulfonic acid metal cation salts of the formula ##STR1## which are useful intermediates to prepare antifolate 5-substituted pyrrolo[2,3-d]pyrimidines. The present invention also relates to a novel process for preparing the sulfonic acid metal cation salts and to a novel process for preparing aldehydes of the formula ##STR2## from the corresponding sulfonic acid metal cation salts.

We claim: 
     
       1. A process for preparing a compound of formula III: ##STR15## wherein: R 2  is NHCH(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  ; R 3  is independently at each occurrence a carboxy protecting group; and   X is a bond or C 1  -C 4  alk-diyl; comprising:     reacting a compound of formula IV: ##STR16## wherein: X and R 2  are defined above for formula III;   M is a metal cation; and   n is 1 or 2; with a trialkylsilyl halide in a solvent.     
     
     
       2. The process according to claim 1 wherein the compound of formula IV is a compound wherein X is a bond, --CH 2  --, or --CH 2  CH 2  -- and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       3. The process according to claim 2 wherein X is --CH 2  --. 
     
     
       4. The process according to claim 1 wherein the compound of formula IV is a compound wherein M is an alkali metal cation, n is 1 and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       5. The process according to claim 4 wherein the alkali metal is sodium. 
     
     
       6. The process according to claim 1 wherein the solvent is acetonitrile, the trialkylsilyl halide is trimethylsilyl chloride, and the reaction is performed at a temperature between 50° C. and 70° C. 
     
     
       7. The process according to claim 6 wherein the compound of formula IV is a compound wherein M is sodium, n is 1, X is --CH 2  --, and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       8. A process according to claim 1 further comprising: a) halogenating a compound of formula III to form a compound of formula V: ##STR17## wherein: R 2  and X are as defined above for formula III; and   halo is chloride, bromide, or iodide; in a solvent; and     b) adding to the product of step a) a base and a compound of formula VI: and ##STR18## c) optionally removing carboxy protecting groups from the product of step b); and   d) optionally salifying the product of step b) or step c) to afford a compound of formula VII: ##STR19## wherein: R is NHCH(CO 2  R 1 )CH 2  CH 2  CO 2  R 1  or OR 1  ; and   R 1  is independently at each occurrence hydrogen or a carboxy protecting group; or a pharmaceutical salt or solvate thereof.   
     
     
       9. A process according to claim 8 wherein the compound of formula V is a compound wherein X is a bond, --CH 2  --, or --CH 2  CH 2  -- and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       10. A process according to claim 9 wherein step a) is performed at a temperature between 35° C. and 45° C. 
     
     
       11. A process according to claim 9 wherein the compound of formula VII is a compound wherein R is NHCH(CO 2  R 1 )CH 2  CH 2  CO 2  R 1 . 
     
     
       12. A process according to claim 11 wherein the compound of formula V is a compound wherein X is --CH 2  --. 
     
     
       13. A process according to claim 12 wherein step c) is performed and the compound of formula VII is the sodium hydroxide base addition salt.